Retinoic acid (vitamin A acid), an active metabolite of vitamin A, has extremely important physiological functions, e.g., inducing differentiation of immature cells under development processes toward mature cells having specific functions, enhancement of cell proliferation, life support action, and the like. Retinoic acid and compounds having retinoic acid-like biological activities are collectively referred to as “retinoids”.
It has been proved that all-trans retinoic acid, considered as a biological retinoid, regulates proliferation and differentiation of animal cells, cellular mortalities, and the like. It has also been revealed that various vitamin A derivatives synthesized so far also have similar physiological functions, for example, the benzoic acid derivatives disclosed in Japanese Patent Unexamined Publication (KOKAI) Nos. 61-22047 and 61-76440, the compounds described in Journal of Medicinal Chemistry, 31 (11), 2182, 1988, and the like. Furthermore, various synthetic retinoids are exemplified in Adv. Drug Res., 24, 81, 1993 and J. Med. Chem., 48, 5875, 2005. For example, it is suggested that 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid (Am80) also exhibits physiological actions similar to (but different from) those of retinoic acid (Cell Structure Funct., 16, 113, 1991; Biochem. Biophys. Res. Com., 166, 1300, 1990). Besides these, it has been demonstrated that various compounds have retinoic acid-like activity, such as the heterocyclic ring-containing carboxylic acid derivatives (Japanese Patent Unexamined Publication No. 9-71566).
For retinoids, various pre-clinical and clinical researches have been conducted for use of them as a medicament for therapeutic or prophylactic treatment of skin diseases, autoimmune diseases, lipid or sugar metabolic disorders, cranial nerve diseases, and malignant tumors. For example, it has been found that they are useful for therapeutic or prophylactic treatment of hyperkaratosis of epithelial tissue, rheumatism, delayed allergy, multiple sclerosis, autoimmune diseases, bone diseases, leukemia, certain types of cancers and cranial nerve diseases, spinal cord injury, cardiovascular diseases such as arteriosclerosis, vasoconstriction or restenosis, and control of neovascularization, diabetes, and disorder of lipid metabolism. As described above, retinoids are characterized by having various biological activities and pharmacological activities, and thus being applicable to various diseases as objects of therapeutic treatment. However, it cannot necessarily be considered that they are practically used as satisfactory medicaments in view of selectivity for the action and action site, kinetics in the living bodies such as that for absorption and excretion, and side reactions, because of such diversity as described above.
Therefore, retinoids exhibiting limited actions, or those showing metabolism, absorption, excretion, and distribution suitable for a specific object of therapeutic treatment are desired. For example, for internal diseases, a retinoid showing less action on the skin is preferred, and for the skin, a retinoid having characteristics suitable for external preparations is desired. Further, for chronic diseases, a retinoid compound showing prolonged action is preferred, for various kinds of cancers, a retinoid which acts on dividing cells such as cancer cells at an optimum concentration different from that for non-dividing cells is preferred, and for cranial nerve diseases, a retinoid having high permeability for the blood-brain barrier, and superior distribution in cranial nerves is desired. Moreover, a retinoid showing less side reactions is desirable as a medicament.
From a viewpoint of chemical compounds, the tert-butyl-substituted furancarboxylic acid derivatives and tert-butyl-substituted thiophenecarboxylic acid derivatives described in Med. Chem. Res., 8, 291, 1998 have been reported as compounds having a structure similar to that of the compounds of the present invention (page 294, Compounds 16a and 16d). However, these compounds have only a weak differentiation-inducing action on the human acute promyelocytic leukemia cell strain HL-60, and thus have extremely weak actions as retinoids.
Non-patent document 1: Med. Chem. Res., 8, 291, 1998 Disclosure of the Invention